Familial adenomatous polyposis (FAP) is an autosomal dominant genetic disorder caused by germline mutations in the APC (adenomatous polyposis coli) gene. FAP is characterized by multiple synchronous and metachronous colorectal adenomas with a 70% to 100% risk of developing colorectal cancer (CRC). Studies have suggested that APC inactivation and epidermal growth factor receptor (EGFR) signaling promote COX-2 expression and the subsequent development of intestinal neoplasia. In a recent double-blind, placebo-controlled, randomized trial (NCT01187901), a non-steroidal anti-inflammatory drug (NSAID), sulindac, in combination with an EGFR inhibitor, erlotinib, effectively reduced the total polyp burden and number in participants with FAP compared with placebo. This effect was significant after 6 months of therapy and was observed in both classic and attenuated FAP participants. However, there was a high rate of adverse events. The most notable were an acneiform rash in 87% of participants and oral mucositis in 39% of participants in the treatment group. During the trial, 54% of patients taking treatment had sulindac-dose reduction at some point during the study. There were 11 patients for whom study drugs were temporarily discontinued due to concern for gastrointestinal bleeding, elevated alanine aminotransferase level, elevated blood pressure, ocular pain or change in vision, and tonsillitis. Though all participants started the trial taking fixed standard doses of the 2 study medications, dose modifications due to intolerance led to a range of doses. Nonetheless, equal efficacy in causing polyp regression was observed across the resulting range of erlotinib doses used, suggesting the erlotinib dose could be lowered while maintaining efficacy. Although the dosing of sulindac was based on prior studies, the dosing of erlotinib was estimated from cancer treatment and lung cancer chemotherapy trials. Other limitations of this study include: no long-term follow-up data, unknown durability of the effect of sulindac and erlotinib, the potential to develop resistance to either drug, and the question as to whether patients ultimately undergo fewer surveillance endoscopies/surgery or develop fewer cancers. Also, both sulindac and erlotinib can be associated with rare and serious adverse effects such as cardiotoxicity and interstitial lung disease respectively. Hence dose-ranging studies are needed to determine if lower and/or less-frequent dosing of sulindac and erlotinib could diminish these adverse effects but retain efficacy. The polyposis in rat colon (Pirc) model has a significant advantage over ApcMin/+ and other Apc mutant mouse models of FAP and CRC, because of its relatively high colon tumor burden, and a lifespan suitable for prevention studies that require an assessment of preventive efficacies and toxicities as well as the development of resistance following long term exposure to chemopreventive agents. In addition, the Pirc model mimics the tumor distribution in FAP patients; the rats develop both small intestinal and colonic tumors, the latter of which can be tracked in individual Pirc rats by periodic endoscopic examinations without sacrificing animals. This model allows an assessment of the effects of chemopreventive agents on both small intestinal and colon tumor types, which have clinically exhibited different transcriptional alterations and sensitivities to agents. However, the toxicity of the two drugs (sulindac and erlotinib) in combination may not allow long term treatment necessary in a prevention setting. Using the Pirc model of small intestinal and colon cancer, the overarching goal of this study is to identify optimal dosing and/or scheduling of sulindac and erlotinib combination regimen that would exhibit lower toxicity while maintaining efficacy in preventing tumor development. A secondary goal is to assess the efficacy of the agents on small intestinal tumors compared to colonic tumors and to develop clinically relevant biomarkers of agent efficacy.